Pro–brain-derived neurotrophic factor (proBDNF) and mature BDNF utilize distinct receptors to mediate divergent neuronal actions. Using new tools to quantitate endogenous BDNF isoforms, we found that mouse neurons secrete both proBDNF and mature BDNF. The highest levels of proBDNF and p75 were observed perinatally and declined, but were still detectable, in adulthood. Thus, BDNF actions are developmentally regulated by secretion of proBDNF or mature BDNF and by local expression of p75 and TrkB.
Summary Experience-dependent plasticity shapes postnatal development of neural circuits, but the mechanisms that refine dendritic arbors, remodel spines, and impair synaptic activity are poorly understood. Mature brain-derived neurotrophic factor (BDNF) modulates neuronal morphology and synaptic plasticity, including long-term potentiation (LTP) via TrkB activation. BDNF is initially translated as proBDNF which binds p75NTR. In vitro, recombinant proBDNF modulates neuronal structure and alters hippocampal long-term plasticity, but the actions of endogenously expressed proBDNF are unclear. Therefore, we generated a cleavage-resistant probdnf knock-in mouse. Our results demonstrate that proBDNF negatively regulates hippocampal dendritic complexity and spine density through p75NTR. Hippocampal slices from probdnf mice exhibit depressed synaptic transmission, impaired LTP and enhanced long-term depression (LTD) in area CA1. These results suggest that proBDNF acts in vivo as a biologically active factor that regulates hippocampal structure, synaptic transmission and plasticity, effects that are distinct from mature BDNF.
Thrombospondins are matricellular proteins that regulate cell-cell and cell-matrix interactions (1, 2). Recent genetic association studies link the thrombospondin (TSP) 2 protein family to the development of atherosclerotic lesions (3-10). TSP-1 was found in early atherosclerotic lesions (11), in injured vascular walls (12,13), and in cardiac allografts where its expression correlated with the degree of vasculopathy (14). The genetic disruption of TSP-1 reduced the atherosclerotic lesion area in the mouse model of atherosclerosis and suggested an important role for TSP-1 in the evolution of plaque and its composition (15). In both in vivo and in vitro studies TSP-1 induced proliferation of vascular smooth muscle cells (SMC) (16,17), and both TSP-1 and TSP-2 inhibited growth of endothelial cells (18 -21); both effects are considered proatherogenic.Previous studies have documented increased TSP-1 levels in the plasma and kidneys of diabetic patients and diabetic animal models (22-25). In mesangial cells, the level of TSP-1 was upregulated by glucose by a transcriptional mechanism (26 -28). We have recently reported increased levels of TSP-1 in the blood vessels of diabetic animals (29). Moreover, TSP-1 was up-regulated by high glucose in vitro in major cell types from large blood vessels. These observations suggest that TSP-1 represents an important link between diabetes, hyperglycemia, and accelerated atherogenesis.A large number of clinical studies and trials have conclusively identified hyperglycemia as an independent risk factor for development of both micro-and macrovascular complications (30 -33). Recently, the Epidemiology of Diabetes Intervention and Complications study reported that, as compared with conventional therapy, intensive glycemic control reduced the risk of the most serious cardiovascular events such as heart attacks, stroke, and death by nearly 60%. These findings clearly underscore the importance of hyperglycemia as a critical player in the development of pathogenic complications associated with diabetes. Glucose regulates the expression of a number of vascular * This work was supported by National Institutes of Health Grants R01 DK067532, K01 DK62128, and P50 HL077107, American Heart Association Grant 0565284B, and funds from the Lerner Research Institute (Cleveland Clinic) (to O. I. S.) and by National Institutes of Health Grant R01 45418 (to P. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Hyperglycemia is an independent risk factor for development of vascular diabetic complications. Vascular dysfunction in diabetics manifests in a tissue-specific manner; macrovasculature is affected by atherosclerotic lesions, and microvascular complications are described as "aberrant angiogenesis": in the same patient angiogenesis is increased in some tissues (e.g. retinal neovascularization) and decreased in others (e.g. in skin). Molecular cell-and tissue-specific mechanisms regulating the response of vasculature to hyperglycemia remain unclear. Thrombospondin-1 (TSP-1), a potent antiangiogenic and proatherogenic protein, has been implicated in the development of several vascular diabetic complications (atherosclerosis, nephropathy, and cardiomyopathy). This study examines cell type-specific regulation of production of thrombospondin-1 by high glucose. We previously reported the increased expression of TSP-1 in the large arteries of diabetic animals. mRNA and protein levels were up-regulated in response to high glucose. Unlike in macrovascular cells, TSP-1 protein levels are dramatically decreased in response to high glucose in microvascular endothelial cells and retinal pigment epithelial cells (RPE). This downregulation is post-transcriptional; mRNA levels are increased. In situ mRNA hybridization and immunohistochemistry revealed that the level of mRNA is up-regulated in RPE of diabetic rats, whereas the protein level is decreased. This cell type-specific posttranscriptional suppression of TSP-1 production in response to high glucose in microvascular endothelial cells and RPE is controlled by untranslated regions of TSP-1 mRNA that regulate coupling of TSP-1 mRNA to polysomes and its translation. The cellspecific regulation of TSP-1 suggests a potential mechanism for the aberrant angiogenesis in diabetics and TSP-1 involvement in development of various vascular diabetic complications.Despite the significant advances in the therapeutic methods to control blood glucose and insulin levels in diabetic patients, the precise regulation of these levels remains a problem. Vascular diabetic complications remain most prevalent and dangerous and account for the greatest numbers of deaths and hospitalizations in diabetic patients. The molecular basis for the vascular complications of diabetes is not well understood. Recent reports indicate that both microvascular and macrovascular complications of diabetes correlate directly with glucose levels in both patients and animal models (1-5). Some of these reports revealed the pathogenic role of impaired glucose tolerance and post-prandial hyperglycemia even in the absence of diabetes, e.g. (6). In vascular cells, glucose regulates expression of many genes that have been linked to the development of atherosclerosis or abnormal angiogenesis (reviewed in Ref. 7). One of them is thrombospondin-1 (TSP-1), 3 a cell matrix protein implicated in both atherogenesis (8 -12) and angiogenesis (13)(14)(15)(16)(17)(18)(19). Several lines of evidence indicate that TSP-1 may represent a lin...
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